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Review
. 2009 Dec;37(Pt 6):1287-92.
doi: 10.1042/BST0371287.

Gene expression networks: competing mRNA decay pathways in mammalian cells

Lynne E Maquat  1 , Chenguang Gong
Affiliations
Review

Gene expression networks: competing mRNA decay pathways in mammalian cells

Lynne E Maquat et al. Biochem Soc Trans. 2009 Dec.

Abstract

Nonsense-mediated mRNA decay and Staufen1-mediated mRNA decay are mechanistically related pathways that serve distinct purposes. In the present article, we give an overview of each pathway. We describe how a factor that is common to both pathways results in their competition. We also explain how competition between the two pathways contributes to the differentiation of C2C12 myoblasts to multinucleated myotubes.

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Figures

Figure 1
Figure 1. Model for NMD
In mammals, newly synthesized CPB80–CBP20-bound mRNA is targeted for NMD once mRNA has been generated by pre-mRNA processing and exported from the nucleus to the cytoplasm. During pre-mRNA processing, splicing results in the deposition of an EJC of proteins upstream of mRNA exon–exon junctions. EJC components include eIF4AIII, Y14, MAGOH (mago-nashi homologue), Barentz (BTZ) and many other proteins. The UPF3 (also called UPF3a) or UPF3X (also called UPF3b) NMD factor is mostly nuclear but shuttles to the cytoplasm and is thought to join EJCs in the nucleus so as to be exported with mRNA to the cytoplasm. In the cytoplasm, UPF3 or UPF3X recruits UPF2. The translation of CBP80–CBP20-bound mRNA constitutes the pioneer round. Translation termination during the pioneer round at a premature termination codon (PTC) that is situated ≥50–55 nt upstream of an exon-exon junction (i.e. ≥25–30 nt upstream of an EJC) involves the SURF complex, which consists of the PI3K-related protein kinase that phosphorylates UPF1, SMG1, together with UPF1, eRF1 and eRF3. As a consequence, NMD generally occurs. During the process, UPF1 together with SMG1 is thought to bind EJC-associated UPF2 in a way that is promoted by CBP80. UPF1 binding to the EJC results in UPF1 phosphorylation. Phospho-UPF1 triggers NMD by promoting translational repression of the NMD target. Translational repression involves the binding of phospho-UPF1 to eIF3 within the 43S pre-initiation complex that is poised at the AUG translation initiation codon so as to prevent 60S ribosomal subunit joining. Phospho-UPF1 also promotes NMD by recruiting mRNA degradative activities. Not shown are SMG5, SMG6 and SMG7, which activate UPF1 dephosphorylation and thus recycling. SMG6 appears to additionally function as an endonuclease. Very recently, roles for SMG8 and SMG9 as SMG1-interacting proteins have been defined [49]. Notably, mammalian-cell NMD can also target mRNAs that have not undergone splicing downstream of a PTC, in a mechanism that has been called failsafe NMD or EJC-dependent NMD, provided that they have undergone a splicing event upstream of the PTC [5,8]. Nucleolytic activities are indicated by the red irregular hexagons. PABP, poly(A)-binding protein, where darker shapes specify the largely nuclear PABPN1 and lighter shapes denote the largely cytoplasmic PABPC1; AUG, translation initiation codon; STOP, normal termination codon; 1, eRF1; 3, eRF3.
Figure 2
Figure 2. Model for SMD
In mammals, SMD targets both newly synthesized CBP80–CBP20-bound mRNAs and the corresponding steady-state eIF4E-bound mRNAs provided they contain an SBS ≥25–30 nt downstream of the normal termination codon. According to current thinking, when translation terminates sufficiently upstream of SBS-bound STAU1, UPF1 binds STAU1. UPF1 binding then triggers mRNA decay, presumably analogously to how UPF1 binding to an EJC during NMD triggers mRNA decay. AUG, translation initiation codon; STOP, normal translation termination codon; PABP, PABPN1 and/or PABPC1 depending on the cap-binding complex.
Figure 3
Figure 3. Model for competition between SMD and NMD: competition contributes to the differentiation of C2C12 myoblasts to myotubes
(A) UPF2, which is an EJC constituent and functions in the classical NMD pathway, and STAU1, which is an RNA-binding protein that functions in the SMD pathway, compete for binding to UPF1 and thus the recruitment of UPF1 to mRNA. UPF1 functions in both pathways to elicit mRNA decay when translation terminates sufficiently upstream of an EJC, in the case of NMD, or STAU1 that is associated with an SBS, in the case of SMD. Ter can be either a premature or a normal termination codon. (B) As a consequence of C2C12-cell differentiation from myoblasts (MBs) to myotubes (MTs), the efficiency of SMD increases, the efficiency of classical, i.e. UPF2-dependent, NMD decreases, and the efficiency of an alternative NMD pathway that relies on UPF3X, but not appreciably on UPF2, increases. During myogenesis, a larger decrease in the abundance of UPF2, which drops to almost undetectable levels relative to STAU1, permits STAU1 to out-compete UPF2 for binding to UPF1, and a ~4-fold increase in the level of UPF3X supports an increase in the efficiency of the alternative NMD pathway.
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